Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
JCR Impact Factor (IF) – 2.1
5-Year Impact Factor – 2.2
Scopus CiteScore – 3.4 (CiteScore Tracker 3.4)
Index Copernicus  – 161.11; MEiN – 140 pts

ISSN 1899–5276 (print)
ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2017, vol. 26, nr 2, March-April, p. 245–249

doi: 10.17219/acem/58784

Publication type: original article

Language: English

Download citation:

  • BIBTEX (JabRef, Mendeley)
  • RIS (Papers, Reference Manager, RefWorks, Zotero)

Vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGFR-3 and D2-40 expressions in primary breast cancer: Association with lymph node metastasis

Aydan Eroğlu1,A,B,C,D,E,F, Cevriye Ersöz2,B,C, Durdu Karasoy3,C, Serpil Sak2,A,C,E

1 Surgical Oncology Unit, Department of General Surgery, Ankara University Medical School, Ankara, Turkey

2 Department of Pathology, Ankara University Medical School, Ankara, Turkey

3 Department of Statistics, Faculty of Science, Hacettepe University, Ankara, Turkey


Background. Two members of the vascular endothelial growth factor (VEGF) family, VEGF-C and -D, are known as lymphangiogenic growth factors and play an important role in tumor lymphangiogenesis via activation of the VEGF receptor (VEGFR)-3, which is expressed in lymphatic endothelial cells. D2-40 is a specific antibody for lymphatic vessel density (LVD).
Objectives. In the present study, we have aimed to evaluate whether intraand peri-tumoral D2-40-positive lymphatic vessels affect lymph node metastasis and to investigate the relationship between LVD and lymph node metastasis in breast cancer.
Material and Methods. We have evaluated the relationships between lymph node metastasis and VEGF-C, VEGF-D, VEGFR-3 and D2-40 expressions in breast cancer cells using immunohistochemistry. VEGF-C, VEGF-D and VEGFR-3 expression were found in tumor cells in the majority of the cases (83.75, 97.5 and 95%, respectively).
Results. There was a significant positive relationship between VEGF-D expression and lymph node metastasis (p < 0.05) however no significant association was found in VEGF-C and VEGFR-3 expressions. It was found that patients with high-expression of VEGF-D have a high level of both periand intra-tumoral LVD compared to those with low expression of VEGF-D (p < 0.05).
Conclusion. Our results support that examination of VEGF-D expression in breast cancer cells may be beneficial in the identification of lymph node metastasis.

Key words

breast cancer, metastasis, VEGF, D2-40

References (23)

  1. Globocan 2012: Estimated cancer incidence, mortality and provalence. Ac-cessed 2015.
  2. Untch M, Gerber B, Harbeck N, et al. 13th St. Gallen International Breast Cancer Conference 2013: Primary therapy of early breast cancer evidence, controversies, consensus-opinion of a German team of experts. (Zurich 2013). Breast Care (Basel) 2013;8:221–229.
  3. Yang C, Liu F, Liu S, Li W, Zhai L, Ren M. Lymph node ratio. A new feature for defining risk category of node-positive breast cancer patients. Int J Surg Pathol. 2012;206:546–554.
  4. Pepper MS. Lymphangiogenesis and tumor metastasis: More questions than answers. Lymphology 2000;33:144–147.
  5. Auwera IV, Cao Y, Tille JC, et al. First international consensus on the methodology of lymphangiogenesis quantification in solid human tu-mours. Br J Cancer. 2006;95:1611–1625.
  6. Valtola R, Salven P, Heikkila P, et al. VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer. Am J Pathol. 1999;154:1381–1390.
  7. Koyama Y, Kaneko K, Akazawa C, et al. Vascular endothelial growth factor-C and vascular endothelial growth factor-D messenger RNA expression in breast cancer: Association with lymph node metastasis. Clin Breast Cancer. 2003;4:354–360.
  8. Hoar FJ, Chaudhri S, Wadley MS, Stonelakc PS. Co-expression of vascular endothelial growth factor C (VEGF-C) and c-erbB2 in human breast carcinoma. Eur J Cancer. 2003;39:1698–1703.
  9. Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathology. 1987;8:138–140.
  10. Ran S, Volk L, Hall K, Flister MJ. Lymphangiogenesis and lymphatic metastasis in breast cancer. Pathophysiology. 2010;17:229–251.
  11. Bando H, Weich HA, Horiguchi S, et al. The association between vascular endothelial growth factor-C, its corresponding receptor, VEGFR-3, and prognosis in primary breast cancer: A study with 193 cases. Oncology Reports. 2006;15:653–659.
  12. Skobe M, Hawighorst T, Jackson DG, et al. Induction of tumor lymphangiogenesis by VEGF-C promotes breast cancer metastasis. Nat Med. 2001;7:192–198.
  13. Raica M, Cimpean AM, Ceausu R, Ribatti D. Lymphatic microvessel density, VEGF-C, and VEGFR-3 expression in different molecular types of breast cancer. Anti Cancer Res. 2011;31:1757–1764.
  14. Liu HT, Ma R, Yang QF, Du G, Zhang CJ. Lymphangiogenic characteristics of triple-negative in node-negative breast cancer. Int J Surg Pathol. 2009;17:426–431.
  15. Swartz MA, Skobe M. Lymphatic function, lymphangiogenesis, and cancer metastasis. Microsc Res Tech. 2001;55:92–99.
  16. Mohammed RAA, Green A, El-Shikh S, et al. Prognostic significance of vascular endothelial growth factors -A, -C, and -D in breast cancer and their relationship with angio- and lymphangiogenesis. Br J Cancer. 2007;96:1092–1100.
  17. Gu Y, Qi X, Guo S. Lymphangiogenesis induced by VEGF-C and VEGF-D promotes metastasis and a poor outcome in breast carcinoma: a retrospective study of 61 cases. Clin Exp Metastasis. 2008; 25:717–725.
  18. Yasuoka H, Nakamura Y, Zuo H, et al. VEGF-D expression and lymph vessels play an important role for lymph node metastasis in papillary thyroid carcinoma. Med Pathol. 2005;18:1127–1133.
  19. Yonemura Y, Endo Y, Tabata K, et al. Role of VEGF-C and VEGF-D in lymphangiogenesis in gastric cancer. Int J Clin Oncol. 2005;10:318–327.
  20. Nakamura Y, Yasuoka H, Tsujimoto M, et al. Lymph vessel density correlates with nodal status, VEGF-C expression, and prognosis in breast cancer. Breast Cancer Res Treat. 2005;91:125–132.
  21. Britto AV, Schenka AA, Moraes-Schenka NG, et al. Immunostaining with D2-40 improves evaluation of lymphovascular invasion, but may not predict sentinel lymph node status in early breast cancer. BMC Cancer. 2009;9:109.
  22. Zhao YC, Ni XJ, Li Y, et al. Peritumoral lymphangiogenesis induced by vascular endothelial growth factor-C and D promotes lymph node metastasis in breast cancer patients. World J Surg Oncol. 2012; 10:165.
  23. Dvorak HF, Weaver VM, Tlsty TD, Bergers G. Tumor microenvironment and progression. J Surg Oncol. 2011;103:468–474.